Method for preparing 4-[17beta-methoxy-17alpha-methoxymethyl-3-oxestra-4,9-dien-11beta-yl]benzaldehyde (E)-oxime (asoprisnil)

ABSTRACT

The present invention relates to a method for the reliable and reproducible preparation of 4-[17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl]benzaldehyde (E)-oxime (asoprisnil) on the pilot and manufacturing scale. Asoprisnil, which is prepared by this method, is distinguished by a very good physical stability and is therefore particularly suitable for the manufacture of solid pharmaceutical forms (tablets, coated tablets, etc.).

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 60/792,643 filed Apr. 18, 2006, whichis incorporated by reference herein.

The present invention relates to a method for the reliable andreproducible preparation of4-[17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(E)-oxime (asoprisnil) on the pilot and manufacturing scale. Asoprisnil,which is prepared by this method, is distinguished by a very goodphysical stability and is therefore particularly suitable for themanufacture of solid pharmaceutical forms (tablets, coated tablets,etc.) which even withstand ICH accelerated conditions (40° C., 75%r.h.).

The preparation of a asoprisnil on the laboratory scale is described forexample in DE 43 32 283 A1; further details on asoprisnil can be foundin EP 0571 15, DE 35 04 42, DE 100 56 675 A1 and DE 100 56 676 A1.

Intermediates for preparing asoprisnil, for example the preparation of3,3-dimethoxyestra-5(10),9(11)-diene-17-one (nordienedione ketal) aredescribed in French patent 151 4 086 and in a publication in “Pharmazie39, No. 7 (1984)” (B. Menzenbach, M. Hübner, R. Sahm, K. Ponsold:“Synthese potentieller Metaboliten der STS 557 (Dienogest)”), thepreparation of3,3,17β-trimethoxy-17α-methoxymethylestra-5(10):9(11)-diene(trimethoxydiene) from nordienedione ketal in EP 0 648 779, EP 0 648778, EP 0 411 733, DD 289539, DE 100 56675, and the preparation ofdienone aldehyde and asoprisnil in DE 43 32 283. EP 129 26 07 describesnovel solid forms of asoprisnil, in particular a high-purity and stableamorphous or highly crystalline form (ansolvate/anhydrate), a method forthe preparation, and the use in pharmaceutical compositions. The solidforms are distinguished in particular by high stability.

These preparation methods describe the principle of the preparation ofthe various intermediates and of the target product, the activeingredient4-[17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(E)-oxime (asoprisnil) on the laboratory scale. Details of reactionconditions for preparing asoprisnil on the pilot or even manufacturingscale are not disclosed in the literature.

According to the details disclosed in the literature, it is not possibleto prepare the individual intermediates on the manufacturing scale insuch a way that the medicinally active asoprisnil and its precursors canbe obtained therefrom reliably and reproducibly and having theanalytical parameters required by the authorities or by the legislationpursuant to ICH Q6A Guidance, 2000, such as byproduct profile, contentof active ingredient, chemical and physical purity, and stability. Thus,although the amorphous solid form described in EP 129 26 07 shows goodstability as pure active ingredient, in the solid pharmaceutical formthere is partial to complete recrystallization under ICH acceleratedconditions (40° C., 75% r.h.). The suitability of the asoprisnilobtainable by this method for a solid pharmaceutical form is accordinglylow.

It is therefore an object of the present invention to provide aproductive and reliable method for preparing asoprisnil with which theactive ingredient can be prepared reproducibly in high purity and yieldon the pilot and manufacturing scale. By purity is meant the physicaland chemical purity of the active ingredient.

This object is achieved by the present multistage method for preparingasoprisnil. It consists of the following stages (see FIG. 1):

In the first stage of the method (see FIG. 2), the synthesis of3,3-dimethoxyestra-5(10),9(11)-dien-17-one (nordienedione ketal) from17β-hydroxyestra-4,9-dien-3-one (hydroxyestradienone), the nordienedioneketal is obtained either

-   -   by oxidation of 17β-hydroxyestra-4,9-dien-3-one        (hydroxyestradienone) to estra-4,9-diene-3,17-dione        (nordienedione) and subsequent selective ketalization to        3,3-dimethoxyestra-5(10),9(11)-diene-17-one (nordienedione        ketal) or    -   by ketalization of hydroxyestradienone to        17β-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy ketal)        and subsequent oxidation to nordienedione ketal.

The second stage of the method, the preparation of3,3,17-trimethoxy-17α-methoxymethylestra-5(10),9(11)-diene(trimethoxydiene) from nordienedione ketal takes place in three stepsvia the stages3,3-dimethoxyestra-5(10),9(11)-diene-17β-spiro-1′,2′-oxirane(nordienespirane) and 3,3-dimethoxyestra-5(10),9(11)-dien-17β-ol(nordiene ether).

In a third stage, trimethoxydiene is converted into the corresponding5α,10α-epoxide (enepoxide) and, in a subsequent Cu(I)-catalyzed Grignardreaction with 4-bromobenzaldehyde dimethyl ketal, converted into theso-called dimethoxy acetal(3,3,17β-trimethoxy-11β-[4-(dimethoxymethyl)phenyl]-17α-methoxy-methylestr-9-en-5α-ol).Reaction of the dimethoxy acetal with acids such as, for example, with85 to 95% strength acetic acid affords4-[17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(dienone aldehyde).

The procedure reduces the formation of byproducts and thus ensures thereproducibility and validatability of each individual step in this stageof the method. The resulting product has a purity which is proved byspecified individual analytical assessments (HPLC purity, UV content),and whose preparation reliably and reproducibly reduces the amounts ofimpurities such as, for example, byproducts of the Grignard reaction(Wurtz products), 11α-aldehyde and 5α-OH aldehyde.

For the final stage, the synthesis of4-[17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(E)-oxime-asoprisnil-dienone aldehyde is reacted with hydroxyaminehydrochloride in organic solvents such as, for example, pyridine ormethylene chloride as described in DE 43 32 283.

The product is subsequently worked up and purified by methods known tothe skilled person, such as, chromatography, fractional filtration orcrystallization, and subjected to a spray drying. It is particularlyimportant in this connection to prepare amorphous asoprisnilmicroparticles which have a high and, in particular, reproduciblephysical purity and stability in the solid pharmaceutical form. It isknown that there is a high risk of recrystallization in the preparationof pure amorphous forms of active ingredients by spray drying, whichrecrystallization may occur in the active ingredient alone or throughcontact with excipients of the pharmaceutical form (Nürnberg, ActaPharmaceutica Technologica, 26, 1980).

Both the crystalline and the amorphous form of asoprisnil described inEP129 26 07 satisfy the requirements to be met by the stability asactive ingredient and for pharmaceutical processing. However, theasoprisnil microparticles must additionally show sufficient stability asactive ingredient (Drug Substance) in the solid pharmaceutical formitself under ICH accelerated conditions. This makes special demands onthe physical purity, which in amorphous structures has a direct effecton the stability thereof in relation to recrystallization. It istherefore indispensable for no detectable recrystallization of thesemicroparticles to occur both during storage of the solid pharmaceuticalform under normal conditions (25° C., 60% r.h.) and under acceleratedconditions (40° C., 75% r.h.). The reliable and, in particular,reproducible preparation of these microparticles makes special demandson the purification and drying of asoprisnil.

The method according to the invention therefore also includes a step fordrying asoprisnil in which a contamination of the microparticles withseed centres is greatly reduced through a suitable procedure.

In every spray drying system dried particles are deposited to a greateror lesser extent on hot inner surfaces of the apparatus, e.g. on thetower wall. It has surprisingly been found that wetting events resultingfrom incompletely vaporized drops which are associated with an onlybrief and localized increase in the ethanol concentration in theparticle layer cause the formation of so-called seed crystals within afew seconds. By seed crystals are meant microscopic or submicroscopiccrystallites or crystalline clusters which are thermodynamically stableand are the starting point for recrystallization processes (I. Gutzow,J. Schnelzer, ‘The Vitreous State’, Springer Verlag 1995, Chapter 9,page 221).

In the present method according to the invention, the spray-dryingprocess is characterized in that the largest drops in the spray coneproduced by the atomizing device are vaporized so rapidly that evenisolated wetting events on surfaces of the apparatus with which theproduct makes contact are very substantially decreased or, better,precluded. This wetting effect is reduced or even precluded to adistinctly higher degree than usual in conventional spray drying.

The size distribution of the drops generated in the atomizing unitdepends on the atomizing device (pressure nozzle, rotating disc, twinfluid nozzle), the geometry thereof, and on the atomization parameters.The twin fluid nozzle generates, for example by comparison with otheratomizing devices, a very fine but very broad range of drop sizes. Therotating disc by contrast a coarser but, on the other hand, narrowerrange of drop sizes. The particle size distribution of the driedparticles is determined by the range of drop sizes.

For use of asoprisnil as drug substance for example in oral low-doseforms it is crucial to generate a particular particle size distribution.On the one hand, the uniformity of content (CUT—Content Uniformity) and,on the other hand, especially for hydrophobic substances of poorsolubility like asoprisnil, the kinetics of dissolution of the activeingredient from the pharmaceutical form must be ensured. Traditionally,a technology with which the dried active ingredient is subsequentlymicronized is generally usual. This takes place preferably in jet millsand means an additional method step associated with high risks for thestability of solids and the purity of phases. The high energy inputfrequently leads to phase transformations or to the generation of seedcentres for phase transformations.

It is known that amorphous substances like asoprisnil often dry fromsolutions to form a solid film on the surface of drops. Onlysubsequently and distinctly more slowly do the liquid contents of theglobule vaporize from a blow-out orifice or by diffusion. The measuredparticle sizes are therefore insubstantially smaller than the drops fromwhich they are formed. This second phase of drying delays the kineticsof drying of large drops even further. Whether a drop can be completelyvaporized and dried to a particle during the spray drying depends notonly on its size but also on the geometric and aerodynamic conditions inthe drying tower, e.g. on the length of the flight path available andthe velocity (Nürnberg, Acta Pharmaceutica Technologica, 26, 1980;Bauckhage, Chem. Ing. Technik 62 (1990), No. 8; Zbicinski, ChemicalEngineering Journal 86, 2002, pp. 207-216).

A further advantageous configuration of the method according to theinvention therefore consists of obtaining the active ingredientasoprisnil after the spray drying in the form of amorphousmicroparticles with a particular particle size distribution in onemethod step without subsequent micronization.

Particularly preferred embodiments of the method according to theinvention are described below, consisting of the following stages:

hydroxyestradienone→nordienedione ketal→trimethoxydiene→dienonealdehyde→asoprisnil (see FIG. 1).

The hydroxyestradienone starting material of the method according to theinvention can be obtained by methods known to the skilled person(Menzenbach, Bernd; Huebner, Michael, Zeitschrift für Chemie (1986),26(10), 371ff).

1. Nordienedione Ketal 1.1. Nordienedione Ketal Via Nordienedione(Hydroxyestradienone→Nordienedione→Nordienedione Ketal) Chromic AcidOxidation of Hydroxyestradienone

The carrying out of chromic acid oxidations in the synthesis of steroidactive ingredients is a synthesis stage which is widely used anddescribed in detail in the specialist literature. Steroidal alcohols areoxidized to ketones using a mixture of chromic acid and sulphuric acid(Jones' reagent, J. Chem. SOC. 1946, 39 and J. Chem. Soc. 1953, 2548).This chromic acid oxidation is carried out in various solvents such asacetone, DMF, dichloromethane and chloroform. DMF and chloroform may inmany cases be replaced by the less physiologically and ecologicallyobjectionable acetone. Disadvantages of this replacement of DMF andchloroform by acetone are the incomplete and non-reproducible conversionof the starting material. For example, unreacted hydroxyestradienone canbe removed only with great difficulty and is therefore “carried over” asimpurity throughout the synthesis of the active ingredient, thus greatlyimpairing the quality of the synthesized product.

Complete and reproducible chromic acid oxidation of hydroxyestradienoneis carried out according to the invention in acetone by managing thereaction as two-phase reaction between liquid phases. To this end, acertain amount of water is added to a solution of hydroxyestradieneonein acetone in such a way that the water content of the organic phasepasses through a minimum in the distribution equilibrium of the waterbetween organic phase and the aqueous chromic acid phase. This minimumarises through the surprising occurrence of a phase change in theinorganic chromic acid phase, which extracts water from the inorganicphase despite an increase in total water content of the reactionsolution. The result of this is that

-   1. the solubility of the organic phase for the steroid is improved,-   2. the chromium sludge cannot trap any starting material because its    viscosity can be instantaneously reduced and-   3. thus a very large mass transfer area can be created by the    agitator.

This minimum is influenced by the temperature and concentrationconditions in the chromic/sulphuric acid. The optimum of theseparameters can be determined experimentally by the skilled person.

The complete and, in particular, reproducible reaction is achieved byadding water, preferably 2-10% by weight based on acetone, to a solutionof hydroxyestradienone in acetone in such a way that a defined systemicwater concentration (added water plus water from the chromic/sulphuricacid), preferably of 10-15% by weight, is adjusted, with the steroidconcentration not exceeding 8 g/l of acetone. The subsequent selectivemonoketalization of the diketone nordienedione is carried out accordingto the invention with Lewis acids according to the following variants:

-   1. Selective ketalization with silicon tetrachloride and methanol    -   a) silicon tetrachloride is put into a mixture of methanol and        n-hexane solvents, with the addition taking place in a        temperature range from −5 to 15° C., preferably 2 to 10° C.;    -   b) rapid addition of nordienedione is in the aforementioned        temperature range from −5 to 15° C., preferably 2° C. to 10° C.;    -   c) stirring during crystallization, where the solution obtained        in b) is preferably stirred at 5° C. to 15° C., particularly        preferably 10° C., for 60 to 100 minutes, and then at −8° C. to        0° C. to complete the crystallization;    -   d) the resulting crystals are isolated using a solid/liquid        separating device and are then washed alternately with methanol        and hexane or methanol/aqueous ammonia    -   e) drying of the resulting nordienedione ketal or-   2. selective ketalization with acetyl chloride and methanol using a    solution of the crude product from the chromic acid oxidation.

The described variants of a specific procedure for the selectiveketalization of nordienedione are distinguished by the formation ofbyproducts being greatly reduced. The said methods afford a productwhich makes specified individual analytical assessments reliably andreproducibly possible and satisfies high quality demands.

1.2. Nordienedione Ketal Via Hydroxy Ketal

In this variant, firstly 17β-hydroxyestra-4,9-dien-3-one(hydroxyestradienone) is ketalized to give the intermediate17β-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy ketal). Thisis followed by oxidation to a nordienedione ketal by Oppenhaueroxidation:

hydroxyestradienone→hydroxy ketal→nordienedione ketal

Purification takes place by usual methods known to the skilled person,for example by chromatography or fractional filtration. Examples thereofwhich may be mentioned are the following solvents such as methanol,heptane, cyclohexane, methyl tert-butyl ether as well as combinationsthereof, and mixtures of solvents such as, for example, methyltert-butyl ether/heptane, cyclohexane/methyl tert-butyl ether,isopropanol/water. Cyclohexane/methyl tert-butyl ether are particularlysuitable.

The support material used for a purification by chromatography is forexample aluminium oxide.

The ketalization with trialkyl orthoformates in methanol is described indetail for steroid active ingredients in the specialist literature(Byer, Walter, Lehrbuch der organischen Chemie, 21^(st) Edition, S.Hirzel Verlag Stuttgart, p. 216).

Steroids which have a keto function in position 3 are converted into thecorresponding dimethyl ketals by using trimethyl orthoformate inmixtures of solvents containing methanol. In conventional ketalizationmethods, sulphuric acid or sulphuric acid derivatives such as, forexample, p-toluenesulphonic acids are added as catalysts. Onedisadvantage of the procedure mentioned is that these catalysts mustsubsequently be removed by extraction. Ketals are unstable under theseaqueously acidic conditions.

The ketalization is therefore carried out according to the invention onan acid-activated ion exchanger. The ion exchanger can be put directlyinto the reaction solution. The advantage of this is that the ionexchanger can easily be removed again by filtration. A further variantof the configuration of the ketalization consists according to theinvention of passing the reaction solution over the acid-activated ionexchanger in a so-called bypass method. This means that removal of theion exchanger is no longer necessary.

Oppenhauer oxidation of steroids is likewise described in detail in thespecialist literature (Byer, Walter, Lehrbuch der organischen Chemie,21^(st) Edition, S. Hirzel Verlag Stuttgart, p. 216). Steroids with a17-hydroxy function are oxidized to the corresponding 17-ketones byusing aluminium alcoholates and cyclohexanone. However, it is notpossible to carry out the reaction hydroxy ketal→nordienedione ketalquantitatively using conventional aluminium alcoholates such as, forexample, aluminium triisopropoxide. For this reason, the reaction iscarried out according to the invention with aluminium diisopropoxidetrifluoroacetate (DIPAT) as catalyst in the presence of cyclohexanone.The hydroxy ketal is reacted virtually completely through the use ofDIPAT.

The nordienedione ketal product of the reaction results as crudeproduct. However, it is possible with conventional methods such as, forexample, recrystallization to achieve a purity of only less than 90%.For this reason, the prepared nordienedione ketal is dissolved accordingto the invention in methyl tertiary butyl ether, filtered throughaluminium oxide and then eluted with a mixture of cyclohexane and methyltertiary butyl ether. The product is obtained with a purity of more than95%.

2. Trimethoxydiene Via Nordienespirane and Nordiene Ether

Nordienespirane is prepared from nordienedione ketal according to DE 10056 675 with trimethylsulphonium iodide and potassium tertiary butoxidein DMF. Nordienespirane is then converted with sodium methanolate inmethanol into nordiene ether. A precondition for its further conversionto trimethoxydiene according to the following sequence

nordienedione ketal→nordienespirane→nordiene ether→trimethoxydieneis that the nordiene ether is isolated and purified in a complicatedmanner.

On further processing in solution, for conversion to be as quantitativeas possible it is necessary to remove as completely as possible from thenordiene ether solution the residues of water and methanol originatingfrom the precursors.

Virtually complete conversion to trimethoxydiene is achieved accordingto the invention by

-   a) carrying out at the nordienespirane stage the reaction in DMF in    an initial phase with addition of the reactants in a temperature    range from 0 to 25° C., preferably between 0 to 20° C. and in an    after-reaction phase between 20 to 40° C., preferably between 30 to    35° C.;-   b) the reaction product obtained in step a) not being isolated but    being employed as solution of nordienespirane in solvents,    preferably in hexane, DMF or in THF;-   c) for conversion of the nordienespirane from step b) into the    nordiene ether changing the solvent, preferably during the reaction    with sodium methanolate, particularly preferably by azeotropic    distillation, and thus reaching the required reaction temperatures    of 70° C. or more;-   d) at the trimethoxydiene stage crystallizing from methanol by    cooling a steroid solution, preferably a solution with 40-50% by    weight steroid, to 20-35° C., preferably 25° C., for about 1 to 2    hours, and then cooling further to −5° C. to −15° C., preferably    −10° C.

Since the water and solvent contents in the starting material forconversion of nordienedione ketal into nordienespirane play asubstantial part, a virtually complete conversion is achieved in thisstage by limiting the amounts of methanol and water, which areconsiderable as a result of the preparation, in the nordienedione ketal.This is ensured when the water content is less than 1%, preferably lessthan 0.6% and the methanol content is less than 1%, preferably less than0.8%, in the nordienedione ketal.

Changing the solvent in the conversion of nordienespirane to nordieneether, for example from hexane to methanol, preferably by azeotropicdistillation, allows the synthesis to be continued without high-loss andcomplicated intermediate isolation of the nordienespirane.

Since the water and solvent contents in the starting material forconversion of nordiene ether into trimethoxydiene play an equally largepart as in the abovementioned conversion of nordienedione ketal intonordienespirane, in this case too complete conversion to trimethoxydieneis guaranteed by reducing the amounts of water and methanol derived fromthe nordiene ether stage, preferably by azeotropic distillation, tobelow 0.8% water, particularly preferably below 0.4% water. Removal ofunreacted nordiene ether is no longer possible later.

The specific temperature control has the effect of distinctly reducingthe formation of byproducts while, at the same time, conversion isvirtually complete and rapid. In particular, the formation of the 17αepimers of nordienespirane and the formation of 16-methyltrimethoxydieneare greatly minimized.

The specific management of the crystallization guarantees a very goodreduction in the amount of byproducts in the crystals. In particular,unreacted nordiene ether and byproducts such as, for example, the17-oxetane compound of the nordiene ketal remain in solution. Theresulting product can very easily be filtered, washed and dried.

3. Dienone Aldehyde Via Enepoxide and Dimethoxy Acetal

Trimethoxydiene is dissolved in dichloromethane and pyridine.Hexafluoroacetone is added as catalyst for the subsequent epoxidation. Ahydrogen peroxide solution is metered in at 25 to 35° C. Afterconversion has taken place, the phases are separated. The organic phaseis, after removal of the peroxides by washing with water, sodiumbicarbonate solution and sodium thiosulphate solution, changed to THF bydistillation. The dimethoxy acetal is prepared by a Grignard reactionfrom enepoxide and magnesium in THF with bromobenzaldehyde dimethylacetal. Bromobenzaldehyde dimethyl acetal is obtained by acetalizationof 4-bromo-benzaldehyde with trimethyl orthoformate in organic solventsuch as, for example, methanol and THF in the presence of an acidiccatalyst, for example sulphuric acid derivatives (e.g.p-toluenesulphonic acid). For this, the reaction is carried out asdescribed under 1.2. with an acid-activated ion exchanger, with theketalization taking place by a bypass method according to the inventionin a preferred variant of the method. As the skilled person is aware,activation of the magnesium turnings for the Grignard reaction, forexample with dibromoethane or DIBAH, may be necessary in somecircumstances. A catalytic amount of copper(I) chloride is added to theGrignard solution, which can be controlled before use for example to atemperature of 10 to 20° C., under inert conditions and with stirring.Subsequently, preferably within less than 60 minutes, a solution of17α-(methoxymethyl)-3, 3-17β-trimethoxy-5α,10α-epoxyestr-9(11)-ene andTHF is added to the stirred Grignard solution at −10° C. to 55° C.,maximally 45° C., and subsequently an after-reaction is carried out atthe same maximum temperature. Working up takes place by methods known tothe skilled person.

4. Asoprisnil 4.1. Synthesis

The stage for preparing asoprisnil as crude product is composedaccording to the invention of the following individual steps:

-   a) a suspension or solution of dienone aldehyde, for example in    pyridine or methylene chloride, is mixed with a solution of    hydroxyamine-hydrochloride in pyridine-   b) the reaction solution obtained in step a) is put at a temperature    of 0-30° C., preferably 20-25° C., into a solvent, preferably ethyl    acetate, methylene chloride or toluene, which is controlled at a    temperature of 5-15° C., with stirring, and acidified with    hydrochloric acid or sulphuric acid;-   c) working up takes place by    -   crystallization by adding methyl tertiary butyl ether to the        solution and thus obtaining a methyl tertiary butyl ether        solvate with 12-20% methyl tertiary butyl ether and subsequently        drying, or    -   filtration, preferably through silica gel, changing to methanol        by distillation, precipitation with water and drying of the        solid obtained in this way.

4.2. Working Up

The working up of the asoprisnil obtained from the synthetic methoddescribed above takes place by HPLC purification and subsequent spraydrying, the procedure for which is described below.

The HPLC purification can be carried out by methods known to the skilledperson.

A solution of asoprisnil in alcohol, preferably in lower alcohols suchas ethanol, methanol and isopropanol, is sprayed with a specifictemperature regime into a spray-drying system as described in WO01/90137. This regime is such that the outlet temperature of the dryinggas is kept at 40° C. to 90° C., preferably 75° C. to 90° C. Moreover,the mass ratio of spraying gas employed to sprayed solution is 1.5 to10, preferably from 2.5 to 5, and the mass ratio of drying gas employedto sprayed solution employed is at least 10, preferably at least 20.Moreover, the dried asoprisnil particles are separated from the dryinggas on a product filter and deposited virtually completely in acollecting vessel. It has been found that the otherwise usual depositionof spray-dried particles via a cyclone surprisingly leads to distinctlymore unstable products in the case of asoprisnil. The deposition of thespray-dried asoprisnil particles on a product filter is therefore aparticularly advantageous embodiment of the invention. The use of fresh,unused filter surfaces for each production run is a further advantageousconfiguration of the invention, since a product with the desiredstability properties is prepared in this way. Even a few ppm ofcrystalline asoprisnil particles lead to a significant destabilizationof the amorphous product. It has emerged that despite thoroughpurification with the usual solvents such as ethanol or methanolsurprisingly small residues of crystalline substances remain in thematerial on the filter which contaminate the amorphous product withcrystal seeds. The spray drying is followed by an after-drying. In thisprocedure, the microparticles are treated under vacuum of <100 mbar,preferably less than 10 mbar, and at a temperature of less than 90° C.,preferably less than 50° C., and/or with flushing with a solvent-freedrying gas for a lengthy period until the alcohol content is less than1%, preferably less than 0.5%, in order to stabilize the amorphousstructure further.

The described procedure results in physically pure and stable amorphousasoprisnil microparticles

The term “physical purity” refers here, in accordance with theliterature (A. Burger, Pharmazie in unserer Zeit 26, 1997, 93), to achemically pure substance which essentially comprises impurities of thesame chemical substance but in a different solid state (polymorphous,amorphous, pseudopolymorphous) only in small amounts. Depending on thetype of substance, these physical impurities can be measuredquantitatively by thermomicroscopy, differential scanning calorimetry(DSC), x-ray powder diffractometry or other methods.

The present invention accordingly relates to a method for the reliableand reproducible preparation, working up and purification of amorphousasoprisnil, which can be carried out on the manufacturing scale. Themethod according to the invention makes it possible to prepareasoprisnil on the pilot and/or manufacturing scale in high purity withan overall yield of crude, i.e. not yet purified, asoprisnil of 58%(gross). Taking account of the active ingredient content in theasoprisnil final product, a yield of 47% (net) is achieved.

Methods previously disclosed for preparing asoprisnil on the laboratoryscale, as published in DE 433 2283, WO 02/38582 and WO 02/38581,disclose yields of between 5 and 23%. Comparison of the yields achievedis possible only with provisos because the syntheses start fromdifferent starting materials and/or take place by different routes.Compared with the methods described in DE 433 2283 and WO 02/38582,which start at a substantially later point, namely3,3-dimethoxy-5α,10α-epoxyestr-9(11)-en-17-one, and compared with themethod described in WO 02/38581, which starts from a likewise laterstarting material-3,3-dimethoxyestra-5(10),9(11)-dien-17-one-, themethod according to the invention, starting from17β-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) via the followingstages

achieves a distinct increase in the yield to 47 or 58%. The methodaccording to the invention surprisingly achieves an improvement in theyield despite conversion of far larger quantities, i.e. on the pilot ormanufacturing scale, than described in the laboratory methods previouslypublished. A further advantage of the method according to the inventionis that each individual stage of the method can be carried out reliablyand reproducibly on the pilot and manufacturing scale.

The method according to the invention for preparing asoprisnil can becarried out in accordance with the following examples, these serving fordetailed explanation without restricting the invention.

The method can be carried out by employing the agitated reactors,distilling apparatuses, crystallizers, centrifuges and dryers customaryin batch-oriented chemical practice.

1. Nordienedione Ketal 1.1. Nordienedione Ketal Via NordienedioneVariant A

12 kg of hydroxyestradienone are dissolved in 180 l of acetone and then7.5 l of water are added. Chromic/sulphuric acid for oxidation isprepared from 50 l of water, 18 kg of chromium trioxide and 12 l ofsulphuric acid. At 15° C., 17.5 l of this chromic/sulphuric acid with260-270 mg of chromium trioxide/ml are added over the course of one hourand then reaction is continued at 22-25° C. for 1 hour. Working up takesplace by the usual methods known to the skilled person (Cr⁶⁺ reductionwith bisulphite, concentration and crystallization from acetone/watermixtures).

33 l of methanol and 46 l of n-hexane are controlled at a temperature of2-10° C. To them are added firstly 1.2 kg of SiCl₄ and then 10 kg ofnordienedione with stirring. After crystallization starts, the mixtureis stirred at 5-15° C. for 1 hour to 1.5 hours and then cooled to 0 to−8° C. and filtered with suction. If crystallization does not startunaided, seeding is also possible in a conventional way. The crystalsare washed on a frit with hexane and ammoniacal methanol. Drying resultsin 80-109% of expected. The qualities which can reliably be achieved areset forth in the specification and are achieved with the methodaccording to the invention, including purity 95 A % (HPLC), proportionof unreacted nordienedione=0.2 A %, largest unspecified by product=1.0 A%.

Variant B

100 g of hydroxyestradienone are introduced into 400 ml of acetone and20 ml of water. A chromic/sulphuric acid solution prepared from 101 mlof water, 35.6 g of chromium trioxide and 32 ml of sulphuric acid ismetered in at an internal temperature of 12° C. in such a way that ¾ ismetered in two hours and the remainder in a further 2 hours. Afterstirring for 30 minutes, excess chromic acid is decomposed by adding 26ml of isopropanol. The change to water is then effected by distillationin vacuo at an internal temperature of 60° C. About 400 ml of water arerequired for this. The precipitated intermediate (nordienedione) isfiltered off with suction and washed with water until neutral.

Nordienedione is then dissolved in 170 ml of methylene chloride andstirred with 3.6 g of kieselguhr for 20 minutes. Kieselguhr is filteredoff and the filtrate is washed 2× with 50 ml of water each time toremove chromium salts. The organic phase is changed to methanol bydistillation in vacuo and concentrated to 300 ml. 440 ml of hexane areadded at an internal temperature of 20° C. The suspension is cooled to5° C. Over the course of one minute, 26 ml of acetyl chloride are addedand then washed with 37 ml of methanol. The starting material dissolves,and the product then precipitates. If necessary, seeding withnordienedione ketal takes place after 3 minutes.

After crystallization has started, the mixture is stirred for 80minutes, then controlled to 5° C. and made alkaline by adding 37 ml of50% strength sodium hydroxide solution. The product (nordienedioneketal) is isolated and washed firstly with a mixture of 320 ml ofmethanol and 13 ml of aqueous ammonia and then with 35 ml of hexane. Itis sucked dry under a nitrogen atmosphere and dried in vacuo. Yield:82.4 g of nordienedione ketal.

1.2. Nordienedione Ketal Via Hydroxy Ketal

66.7 kg of hydroxyestradienone are dissolved in 500 l of toluene and 400ml of methanol. Filtration through 3.4 kg of activated carbon is carriedout where appropriate. Addition of 51 l of trimethyl orthoformate and afurther 70 l of methanol is followed by circulation by pump over 33.4 kgof activated ion exchanger at 30° C. until conversion to hydroxy ketalis complete. Addition of 20 l of pyridine and 400 l of a sodiumcarbonate solution is followed by stirring and separation of the phases.The aqueous phase is back-extracted several times with 135 l of toluene.The combined organic phases are concentrated to 300 l and changed to 300l of toluene by distillation.

40 kg of aluminium isopropoxide and 180 l of heptane are introduced intoa second reaction vessel. 14.7 l of trifluoroacetic acid are metered inat a temperature of 50° C. Addition of 6.7 l of pyridine is followed byremoval of heptane by distillation down to 95 l. After cooling to ≦25°C., the organic hydroxy ketal solution is added while stirring. Additionof a total of 76 l of cyclohexanone, metered in part, is followed bystirring for up to 6 hours until conversion is complete. Addition of 570l of a sodium hydroxide solution is followed by stirring and separationof the phases. The aqueous phase is back-extracted several times with 70l of toluene. The combined organic phases are washed several times with70 l of water. The mixture is concentrated to 270 l and changed to waterby distillation. This results in 270 l of a suspension of crude productand water. The crude product is isolated and dissolved in 270 l ofmethyl tert-butyl ether. The solution is washed with 70 l of water. Theaqueous phase is back-extracted with 70 l of methyl tert-butyl ether.The combined organic phases are filtered and concentrated to 135 l.After addition of 540 l of cyclohexane, the solution is filtered through134 kg of aluminium oxide. The aluminium oxide is washed with a mixtureof a total of 270 l of cyclohexane and 100 l of methyl tert-butyl ether.The product-containing fractions are concentrated and changed to 200 lof heptane by distillation. The heptane solution is cooled to −15° C.,whereupon the product crystallizes. The product is isolated and washedwith 35 l of heptane and 35 l of water. The nordienedione ketal productis dried at max. 40° C. until the loss on drying is ≦0.5%.

2. Trimethoxydiene Via Nordienespirane and Nordiene Ether

65.6 kg of nordienedione ketal and 50 kg of trimethylsulphonium iodideare suspended in 1501 of dimethylformamide (DMF) and cooled to 15° C. Asolution of 30 kg of potassium tert-butoxide in 65 l of DMF is meteredin at 20° C. The mixture is stirred at 30° C. for 30 minutes and theconversion is checked by TLC. 200 l of water and 410 l of hexane areadded at 30 to 40° C. to transfer the reaction product into the hexanephase. The aqueous DMF phase is back-extracted four times with 50 l ofhexane each time. The combined organic phase is washed twice with 85 lof water. The aqueous phase is back-extracted with 50 l of hexane.Subsequently concentrated in vacuo to a volume of 150 l and mixed with130 l of methanol. About 250 l of sodium methanolate solution (30%) areadded to the methanolic solution, and distillate is taken off underatmospheric pressure until at least 70° C. is reached. The mixture isthen heated under reflux for 1.5 hours until the conversion is complete.Distillation is continued in vacuo with continuous addition of 215 l ofwater. The nordiene ether obtained in this way is taken up in 330 l ofmethyl tertiary butyl ether (MtBE), the organic phase is separated offand the aqueous phase is extracted twice with 100 l of methyl tertiarybutyl ether each time. The combined organic phases were extracted twicewith 100 l of water. The aqueous phases were back-extracted with 60 l ofMtBE. This is followed by concentration in vacuo and, at a volume of 165l, water and methanol are removed azeotropically from the organic phasewith the addition of 165 l of methyl tertiary butyl ether to maintainthis volume. 27.2 l of methyl iodide and 10 l of MtBE are added thereto.Then 70.5 kg of potassium tertiary butyl ether in 300 l of MtBE aremetered in at 35° C. Reaction is continued for 1 to 2 hours, and theconversion is checked. After addition of 245 l of water, the organicphase is separated off and washed with 65 l of water. The aqueous phaseis back-extracted with 65 l of MtBE. This is followed by concentrationto about 80 l in vacuo. Distillation to change to methanol andconcentration to a volume of 140 l are followed by stirring at 25° C.for 1 to 2 hours. The mixture is then cooled to below −10° C. andstirred for a further 2 hours. The product is subsequently isolated andwashed with 15 l of cold methanol. Trimethoxydiene is dried in vacuo at40° C.

3. Dienone Aldehyde Via Enepoxide and Dimethoxy Acetal 3.1. Enepoxide

10.6 l of hexafluoroacetone are added to a solution of 80.6 kg oftrimethoxy diene, 755 l of methylene chloride and 11 l of pyridine. 81 lof a 35% strength hydrogen peroxide solution are gradually added to thissolution while stirring at a temperature of 30 to 40° C. After theaddition, the mixture is stirred at 30 to 40° C. for 30 min and then acheck of conversion is carried out. The organic phase is separated offand washed twice with 175 l of aqueous sodium bicarbonate solution. Theorganic phase is subsequently washed with 250 l of sodium thiosulphatesolution. Finally, the organic phase is washed three to four times with160 l of water. The organic phase washed in this way is concentrated invacuo and at a temperature of 30° C. and changed to THF by distillationso that the final volume is 170 l.

3.2. Dimethoxy Acetal

The Grignard reagent is prepared from 13 kg of magnesium turnings, 280 lof THF, 7.3 kg of DIBAH and 106 l of bromobenzaldehyde dimethyl acetal.Bromobenzaldehyde dimethyl acetal is prepared by acetalization of4-bromo-benzaldehyde with trimethyl orthoformate in methanol in thepresence of acidic catalysts, preferably acidic ion exchanger,preferably in a bypass method. After addition of about 0.5 kg ofcopper(I) chloride, the enepoxide solution is added, the mixture isstirred at 40° C. until conversion is complete. Excess Grignard reagentis destroyed by metering in 490 l of ammonium chloride solution at max.10° C. After addition of 142 l of dilute acetic acid, the organic phaseis washed 3 to 4 times with 122 l of ammonium chloride solution. Theaqueous phases are back-extracted three to four times with 90 l of ethylacetate. The combined organic phases are washed with 170 l of sodiumchloride solution and concentrated to 220 l in vacuo at 40° C.

3.3. Dienone Aldehyde

The dimethoxy acetal solution is mixed with 312 l of conc. acetic acidand 35 l of water and heated at 90° C. for about 30 min. After cooling,680 l of water are metered in. The crude product is isolated and stirredand washed several times with 170 l, 170 l and 110 l and 340 l of MtBether at temperatures up to 50° C. Dienone aldehyde is dried in vacuo at30° C. to 40° C.

4. Asoprisnil 4.1. Synthesis Variant A

15 kg of dienone aldehyde are suspended in 38 l of pyridine. To this areadded 42 l of a prepared hydroxyamine hydrochloride/pyridine solution.After a successful check of conversion and taking up in 88 l of ethylacetate, 6N HCl is added while monitoring the pH (2-4). After phaseseparation and extraction of the organic phase with water, the organicethyl acetate phase is concentrated, distilled with toluene andsubsequently mixed with 50 l of methyl tertiary butyl ether.Crystallization results in the target product. It is then dried.

The following purities were achieved with the method according to theinvention after HPLC examination:

Oxime=92.9 area %Aldehyde=0.08 area %

Z-Oxime=3.1 A % Dioxime=3.1 A % Variant B

50 kg of dienone aldehyde are dissolved in 250 l of methylene chloride.A solution of 8.86 kg of hydroxyamine hydrochloride in 130 l of pyridineis added at 20° C. over the course of 1 to 2 h. After a successful checkof conversion, about 280 l of sulphuric acid are metered in at <10° C.At 10° C., the phases are separated and the aqueous phase isback-extracted twice with 120 l of methylene chloride. The organic phaseis washed three times with 200 l of water, which are back-extracted with110 l of methylene chloride. The organic phase is concentrated to 200 lin vacuo and filtered through silica gel. The organic phase is washedwith about 100 l of a sodium bicarbonate solution. Distillation iscarried out in vacuo to change to a final volume of 200 l of methanol.The methanolic product solution is added to 510 l of water, whereuponthe crude product precipitates. Asoprisnil (crude) is isolated and driedin vacuo at 30 to 40° C.

The crude product is purified by preparative high performance liquidchromatography (HPLC). For this purpose, the asoprisnil (crude) isdissolved in dichloromethane and applied to silica gel. The substance isthen eluted with a toluene/acetone mixture. A mixed fraction is obtainedin addition to the pure fraction and can be rechromatographed toincrease the yield. The pure fraction is concentrated and isolated inthe next process step.

4.2. Working Up and Purification EXAMPLE 1

5.1 kg of asoprisnil are dissolved in 57 l of ethanol (DAB) by heatingto 60° C. The clear solution is pumped with minimal pulsation by ametering pump at 6 l/h to the twin-fluid nozzle (d=0.8 mm) of a spraydryer, cylinder d=800×620 mm, base cone 60°, co-current operation ofheating and spraying gas. The asoprisnil solution is maintained at atemperature of 65° C. during this. The atomizing gas is adjusted at thenozzle to 12 Nm³ N₂/h. The heating gas throughput is 85 m³/h. Theheating gas inlet temperature is adjusted so that the outlet temperatureat the dryer is 78° C. to 85° C. The dried microparticles are depositedon fresh textile filters with PTFE membrane of 1 m². For this purpose,the surface of the filter is periodically pulsed free withcounter-current nitrogen. After the spray-drying process, the asoprisnilpowder is subjected to an after-drying process. For this purpose, thedrying chamber is alternately subjected to a vacuum of 5 mbar andflushing nitrogen heated to 45° C. The vacuum and flushing phases eachlast 45 min. The drying time is 12 h, and the final product temperaturereached is 35° C. The asoprisnil microparticles obtained in this way areanalyzed and show the following characteristics:

Residual solvent content: 0.36% ethanol Particle distribution: d₅₀ = 2.1μm, d₁₀₀ = 21 μm Enthalpy of fusion (DSC at 5 K/min) 4.1 J/g (see FIG.3) Number of crystallites at 170° C. 1187 crystallites per mg XRPDamorphous, no crystalline reflections

EXAMPLE 2

25 mg film-coated tablets in PVC-Al blister packs with pharmaceuticallycustomary excipients and with 16% active ingredient according to example1, which shows by DSC with a heating rate of 5 K/min an enthalpy offusion of 4.1 J/g and by thermomicroscopy a crystallite number of 1187per mg, are stored at 40° C., 75% r.h. as specified in the ICHguideline.

Stability analysis with XRPD

After 9 months at 40° C., 75% r.h.: amorphous

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1 and 2 show synthesis of the invention, and

FIG. 3 shows a DSC curve for a product.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding U.S. Provisional Application Ser. No.60/792,643, filed Apr. 18, 2006, is incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1) Method for preparing asoprisnil on the pilot or manufacturing scale via the stages

comprising the following steps: a) synthesis of nordienedione ketal from hydroxyestradienone either by oxidation of 17β-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) to estra-4,9-diene-3,17-dione (nordienedione) and subsequent selective ketalization to 3,3 dimethoxyestra-5(10),9(11)-diene-17-one (nordienedione ketal) or by ketalization of hydroxyestradienone to 17β-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy ketal) and subsequent oxidation to nordienedione ketal. b) synthesis of trimethoxydiene from nordienedione ketal in three steps via the stages 3,3-dimethoxyestra-5(10),9(11)-diene-17β-spiro-1′,2′-oxirane (nordienespirane) and 3,3-dimethoxy-17α-methoxymethylestra-5(10),9(11)-dien-17β-ol (nordiene ether), not isolating nordienespirane and nordiene ether, c) synthesis of 3,3,17β-trimethoxy-11β-[4-(dimethoxymethyl)phenyl]-17α-methoxymethylestr-9-en-5α-ol (dimethoxy acetal) from trimethoxydiene via 17α-(methoxymethyl)-3,3,17β-trimethoxy-5α, 10α-epoxyestr-9(11)-ene (enepoxide) in a Cu(I)-catalyzed Grignard reaction with bromobenzaldehyde dimethyl acetal d) synthesis of the dienone aldehyde by reaction with acids e) synthesis of asoprisnil from dienone aldehyde with a hydroxyamine hydrochloride solution, f) purification by chromatography, g) drying. 2) Method according to claim 1, where hydroxyestradienone is converted into nordienedione ketal by ketalization with Lewis acids and either by chromic acid oxidation or Oppenauer oxidation. 3) Method according to claim 2, where either the hydroxyestradienone is first oxidized and then ketalized or is first ketalized and then oxidized. 4) Method according to claim 3, carrying out the chromic acid oxidation first and a selective ketalization subsequently or the ketalization first and an Oppenauer oxidation subsequently. 5) Method according to claim 3, where the chromic acid oxidation is carried out as two-phase reaction between two liquid phases. 6) Method according to claim 5, where water, preferably 2-10% by weight based on acetone, are added to a solution of hydroxyestradienone in acetone in such a way that a defined systemic water concentration, preferably of 10-15% by weight, is set up, with the steroid concentration not exceeding 8 g/l of acetone. 7) Method according to claim 3, where the ketalization is carried out first, preferably on an acidic ion exchanger. 8) Method according to claim 7, where the ketalization takes place in a bypass method. 9) Method according to claim 3, where the Oppenauer oxidation takes place with catalysis by aluminium diisopropoxide trifluoroacetate (DIPAT). 10) Method according to claim 1, where nordienedione ketal is converted completely to trimethoxydiene via the stages of nordienespirane and nordiene ether in three steps, characterized by a) carrying out at the nordienespirane stage the reaction in DMF in an initial phase with addition of the reactants in a temperature range from 0 to 25° C., preferably between 0 to 20° C. and in an after-reaction phase between 20 to 40° C., preferably between 30 to 35° C.; b) the reaction product obtained in step a) not being isolated but being employed as solution of nordienespirane in solvents, preferably in hexane, DMF or in THF; c) for conversion of the nordienespirane from step b) into the nordiene ether changing the solvent, preferably during the reaction with sodium methanolate, particularly preferably by azeotropic distillation, and thus reaching the required reaction temperatures of 70° C. or more; d) at the trimethoxydiene stage crystallizing from methanol by cooling a steroid solution, preferably a solution with 40-50% by weight steroid, to 20-35° C., preferably 25° C., for about 1 to 2 hours, and then cooling further to −5° C. to −15° C., preferably −10° C. 11) Method according to claim 1, where the drying in step g) takes place in such a way that contamination of the dried asoprisnil microparticles with seed centres in the drying device is greatly reduced. 12) Method according to claim 11, where the drying preferably takes place by a spray drying, characterized in that a narrow particle size range is achieved through the geometrical and aerodynamic conditions in the atomizing device, and wetting events by spray drops on surfaces of the apparatus with which the product makes contact are avoided. 13) Method according to claim 11, in which the narrow drop size range is generated by a high atomizing efficiency of the spraying unit by maintaining a mass ratio of spraying gas employed to sprayed solution of from 1.5 to 10, preferably from 2.5 to 5, and a mass ratio of drying gas employed to sprayed solution employed of at least 10, preferably at least 20 and with a drying temperature of from 40° C. to 90° C., preferably 75° C. to 90° C. 14) Method according to claim 13, where the high atomizing efficiency of the spraying unit is produced by a high speed of rotation of a rotating disc or by a high atomizing gas throughput through a twin-fluid nozzle. 15) Method according to claim 11 such that the spray-dried asoprisnil microparticles are subjected to an after-drying procedure which takes place in vacuo and/or with flushing of the asoprisnil microparticles with a solvent-free drying gas below 90° C., preferably below 50° C., for at least 12 h. 16) Method according to claim 11, where the deposition of the asoprisnil microparticles after the spray drying takes place on a product filter, preferably using fresh unused filter surfaces. 17) Amorphous, physically pure asoprisnil microparticles obtainable by a method according to claim
 1. 18) Asoprisnil microparticles according to claim 17 having an average particle size d₅₀ of less than 2.5 μm, preferably 2.1 μm, and a maximum particle size d₁₀₀ of less than 25 μm, preferably 11 μm. 19) Asoprisnil microparticles according to claim 17, characterized in that the enthalpy of fusion at 194.7° C.±2° C., determined by DSC with a heating rate of 5 K/min, is less than 20 J/g, preferably less than 5 J/g, preferably less than 1 J/g. 20) Asoprisnil microparticles according to claim 17, characterized in that, when they are heated at 20 K/min to 170° C. and then cooled at 20 K/min to 90° C., the number of crystallites visible by thermomicroscopy is less than 10 000 per mg, preferably less than 4000 per mg, particularly preferably less than 1000 per mg. 21) Asoprisnil microparticles according to claim 17 for the manufacture of medicaments. 22) Use of asoprisnil microparticles according to claim 21 for the manufacture of a medicament for the treatment of hormone-dependent gynaecological disorders, especially for the treatment of endometriosis, fibroids or other gynaecological dysfunctions. 23) Use of asoprisnil microparticles according to claim 17 in hormone replacement therapy (HRT) and for female fertility control. 24) Pharmaceutical composition comprising asoprisnil microparticles according to claim 17 together with pharmaceutically acceptable excipients and/or carriers. 25) Pharmaceutical composition according to claim 24 characterized in that the composition is a solid pharmaceutical form. 26) Solid pharmaceutical form according to claim 25, characterized in that administration takes place orally. 